Effects of aromatase inhibitor 4-hydroxyandrostenedione and other compounds in the 7, 12-dimethylbenz(a)anthracene-induced breast carcinoma model.
Aromatase inhibitor, 4-hydroxyandrostene-3,17-dione (4-OHA), is a highly effective treatment in rats with 7,12-dimethylbenz(a) anthracene-induced hormone-dependent mammary tumors. Over 90% of tumors regress to less than one-half of their original size, and a high proportion regress completely. Treatment of rats with other inhibitors, 4-acetoxyandrostene-3,17-dione and 1,4,6-androstatriene-3,17-dione produce similar results. In comparison with other aromatase inhibitors, the compounds reduced ovarian estrogen secretion in the rat to the same extent as aminoglutethimide, whereas Teslac was without effect. The latter two compounds caused little and no regression of DMBA-induced mammary tumors, respectively. Our recent studies with 4-OHA, 4-acetoxyandrostene-3,17-dione, and 1,4,6-androstatriene-3,17-dione indicate that they interact with aromatase by a two-component mechanism, a rapid competitive inhibition, and a slower enzyme inactivation. Treatment of rats with 4-OHA also caused greater than 80% loss of ovarian aromatase activity in vivo and a reduction in ovarian estrogen secretion, which are maintained for at least 48 hr after injection. Although 4-OHA is cleared rapidly in vivo, the above results suggest that the compound has a sustained effect. Thus, when 7,12-dimethylbenz(a)anthracene-induced tumor-bearing rats were treated with 4-OHA injections on alternate weeks, tumor regression continued to occur during weeks without treatment. The overall regression was similar to that with continuous treatment. 4-OHA is also effective and similar to ovariectomy in rats with hormone-dependent metastatic mammary tumors produced by nitrosomethylurea. Our results indicate that mammary tumor regression induced by 4-OHA is mainly the result of the inhibition of aromatization, although other activities of the compound may also contribute.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000733:Androstatrienes / Q000494:pharmacology; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D002369:Castration; D004967:Estrogens / Q000378:metabolism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008770:Methylnitrosourea; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D010053:Ovary / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats
D000733:Androstatrienes; D047072:Aromatase Inhibitors; D004967:Estrogens; C011658:androsta-1,4,6-triene-3,17-dione; D000735:Androstenedione; D015127:9,10-Dimethyl-1,2-benzanthracene; C022569:4-acetoxy-4-androstene-3,17-dione; D008770:Methylnitrosourea; D010088:Oxidoreductases; C014594:formestane